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A trial published in JAMA asks exactly this question, the full text can be found here. The abstract is below, but as we always say, please read the full paper yourself.
Previous studies have shown that calcium has both an inotropic and a vasopressor effect (although when looking for evidence most of this is animal based studies) . Alongside this, calcium also plays a role in the treatment of life threatening hyperkalemia, one of the key “H’s” in the 4H and 4T mantra of ALS. So there are pathophysiological arguments as to why it might seem a good idea to include in the management of cardiac arrest patients.
What question does the trial look to answer?
Does the use of calcium in an OHCA improved sustained return of spontaneous circulation (ROSC)? This was defined as ROSC for at least 20 minutes.
This is not a patient centred primary outcome, secondary outcomes did include 30 day survival and favourable neurological outcome at 30 days. Is having ROSC for 20 minutes clinically important? Does it change our management or ongoing plan for patients coming to the Emergency Department in cardiac arrest?
I would have loved to have seen 30 day survival or neurological outcome being a primary objective. It is much more relevant to the patient. It could be argued that survival for out of hospital cardiac arrests is so low that the sample size to power such an outcome would have been unobtainable. So survival to ROSC is a more pragmatic way of conducting this study.
What did this trial do?
Any adult (>18) with an OHCA who had received one dose of epinephrine was recruited into this study. They were randomised to:
Intervention group: received a dose of Calcium Chloride 5mmol IV/IO (200mg of calcium), given after the first ACLS dose of epinephrine. A further dose of calcium was given after the second ACLS epinephrine if the patient was still in cardiac arrest.
Control Group: received a dose of sodium chloride after the first and second ACLS ephinephrine
Patients with suspected hyperkalemia or hypocalcemia cause of their cardiac arrest were excluded along with the usual exclusions of pregnant patients and traumatic cardiac arrests. It’s important that patients in which we know calcium is a valid and useful treatment for underlying disease such as hypocalcemia were excluded from this trial. I think the inclusion of these patients would have bias the data. Excluding these patients means we are looking at the potential benefit of calcium in undifferentiated cardiac arrest patients.
This trial ticks a lot of positive trial methodology boxes. The randomisation was blinded to the patient, investigator and clinical teams. It was placebo controlled and set up as a superiority trial.
Base line characteristics for patients in the control and intervention group were similar with no huge outliers.
Patients with non shockable rhythms made up the bulk of this trial. 150 in the calcium group and 145 in the control. The calcium intervention group had 43 patients with shockable rhythms vs 53 in the saline control group. Non shockable out of hospital cardiac arrests have low survival rates compared to shockable, this difference in presentation could bias the results.
What were the results?
397 cases were included in the results analysis, with 73% of patients in the intervention group receiving both doses of calcium.
Primary outcome of ROSC:
19% calcium group (37/139) vs 27% (53/198) saline group
p value 0.09, 95% CI -16% to 0.8%
Secondary outcome 30 day survival
5.2% calcium group (25/193) vs 9.1saline (18/198)
p value 0.17, 95% CI -9.4% to 1.3%
This trail was stopped early due to an independent data monitoring group having safety concerns. The trial did not recruit the 674 patients needed to power this study. We also know that trails that are stopped early tend to overestimate any effects of the data. So this trial is under powered with the potential results having overestimated any effect. Results should be read with this caution.
Were there any adverse events?
Adverse events were looked at for the patients who obtained ROSC. Hypercalcemia was found in 26 of the 37 patients in the intervention group with 14 of those patients classified as having moderate ( 1.47-2.00 mmol/L) hypercalcemia compared to 1 patient in the control group having mild hypercalcemia. This trend was also found in the patients who survived at least 24 hours. This is perhaps unsurprising that if we administer calcium in a cardiac arrest we may end up giving our patient high calciums.
Tachyarrythmias were also recorded in patients who survived at least 24 hours with 12/53 patients in the control group vs 7/37 in the intervention group suffering from an arrhythmia. It’s also worth noting that calcium was given after an average of 17 minutes which some might argue is too long to be effective.
The administration of Calcium in OHCA does not improve ROSC or 30 day survival. The data may actually trend to the use to calcium causing harm. Our view is that calcium should only be used in cardiac arrest if the clinicians specifically suspect hypocalcaemia as a cause or for its use as an antidote/treatment.
- Vallentin et al. Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA 2021 Dec 14;326(22):2268-2276. doi: 10.1001/jama.2021.20929.